This invention relates generally to transdermal drug delivery systems, and more particularly to pressure-sensitive adhesive compositions, that incorporate polyoxaline polymers to inhibit crystal formation and degradation of the active agent in the carrier composition during storage, and improve the delivery rate of the active agent.
The use of transdermal drug delivery systems or “patches” as a means to topically administer a drug is well known. Such systems incorporate the drug into a carrier composition, such as a polymeric and/or pressure-sensitive adhesive composition, from which the drug is delivered at therapeutically effective amounts by absorption through skin or mucosa of the user. Such transdermal systems are described, for example, in U.S. Pat. Nos. 4,814,168; 4,994,267; 5,474,783; and 5,656,286, all of which are expressly incorporated by reference in their entireties.
Transdermal systems that incorporate solid or crystalline forms of drugs require that such drugs be dissolved in the polymeric and/or pressure-sensitive adhesive composition in order to deliver a therapeutically effective amount. The ability of a transdermal system to deliver a therapeutically effective amount for the intended duration of use therefore requires that the active agent remain in non-crystalline or dissolved form in the carrier composition prior to use.
It has been shown that the degree of saturation and solubility of the active agent in the carrier composition are determining factors in controlling delivery of the active agent from the transdermal system. Since only solubilized active agent is available for delivery out of the transdermal system, the carrier composition must not promote drug crystal growth or formation, especially during storage of the system prior to use. It is known that the chemical reactivity between the various components making up the drug carrier composition can significantly affect the drug's solubility in the carrier compositions. For example, many transdermal systems use a pharmaceutically acceptable acrylic polymer as the means to contain the drug. However, it has been found that the functionality and monomeric make-up of such adhesives can significantly affect the drug's solubility in the carrier compositions.
Development of transdermal systems is further frequently hampered by poor solubility of certain active agents in the carrier composition, which in turn also severely limits its therapeutic application. The tendency for crystal formation or growth is known, for example, in the case of high melting point hydrophobic drugs, such as hormones and steroidal active agents, which tend to be poorly soluble or insoluble in polymeric compositions because they form strong crystal bonds.
Failure to control crystal formation and growth can further interfere with the physical properties of the transdermal system. This aspect is particularly important in matrix-type systems because the carrier composition has to be optimized not only to incorporate and administer the desired active agents, but also to obtain sufficient wear properties (means of attachment to the user) for the adhesive carrier. While using low concentrations in order to incorporate the active agent into the carrier may not deleteriously affect the carrier's adhesive properties, low active agent concentration can result in difficulties in achieving an acceptable delivery rate. Poor or inadequate solubility of the active agent can further give rise to crystal formation or growth. Furthermore, surface crystals can come into direct contact with the skin or mucosa and promote irritation.
Generally, concentrations of the active agent substantially at or near the saturation solubility, and even supersaturated (i.e., an amount of active agent at a concentration greater than the solubility of the active agent in the carrier composition at room temperature) are sought in order to increase or maximize delivery rates. Such systems are also desirable because they provide the ability to potentially achieve continuous administration of the active drug in therapeutically effective amounts for prolonged periods of time, such as up to 3 days, and even up to 7 days or more. In these systems, however, the active agent can more easily recrystallize, especially during storage. Crystallization may occur after a few weeks or months of storage.
Active agent that is present in crystalline form cannot be delivered through skin or mucosa, which will accordingly alter drug flux upon application to the user. Inadequate delivery of the active agent in turn leads to blood levels falling below that which are therapeutically effective. The presence of drug crystals is therefore generally undesirable.
The ability of a transdermal system to deliver a therapeutically effective amount for the intended duration of its use further requires that the drug remain stable in its active form (i.e., not substantially decompose, change form or convert into undesirable by-products, metabolites, enantiomers, or substantially inactive or non-therapeutic forms of the drug).
Many transdermal systems rely upon enhancers to improve or increase drug penetration or permeation at the site of topical application of the system. However, certain enhancers may react with drugs to cause their degradation into by-products that can interfere with drug penetration and delivery. See, for example, U.S. Pat. No. 6,024,974.
To prevent drug crystallization and degradation in transdermal systems, compounds which in individual cases have been described in the art as crystallization inhibitors and/or used to improve the storage stability of transdermal systems include PVP, cellulosic polymers, polyethylene oxide, polyvinyl alcohol, polyacrylic acid, gelatins, cyclodextrins, silica, silicon dioxide, starch (derivatives) and dextran. Although the addition of solubilizing agents, such as PVP, help to inhibit crystallization, there are some applications where it is desirable to have greater crystal inhibiting effects or obviate the need for adding a drug degradation inhibitor or stabilizing agent as well.
It has been found that polyoxaline polymers [Poly (2-ethyl-2-oxazoline] are suitable to both suppress or prevent crystal formation and degradation of active agents in transdermal systems, and additionally provide very good in vitro flux rates, particularly with hydrophobic drugs.